|Publication number||US4557764 A|
|Application number||US 06/648,001|
|Publication date||Dec 10, 1985|
|Filing date||Sep 5, 1984|
|Priority date||Sep 5, 1984|
|Also published as||CA1260650A, CA1260650A1, EP0174175A2, EP0174175A3|
|Publication number||06648001, 648001, US 4557764 A, US 4557764A, US-A-4557764, US4557764 A, US4557764A|
|Original Assignee||Collagen Corporation|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (5), Referenced by (93), Classifications (14), Legal Events (8)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present invention relates to preparation of collagen for medical or other associated uses. More specifically, the invention relates to preparation of a collagen composition which is malleable and which has desirable physcial properties.
Preparations of collagen have found use in a variety of therapeutic and reconstructive contexts in both soft tissue and bone, as well as in the preparation of surgical sponges and associated accessories for medical use.
Collagen is the major protein of the skeletal system, and is found in bone, skin, and cartilage. Native collagen consists in large part of a triple helical structure which appears to be a consequence of repeating triplet sequences composed of glycine linked to two additional amino acids, commonly proline and hydroxyproline, the glycine being in every third position in the chain. In addition, all collagen chains contain regions at each end which do not have the triplet glycine sequence and are thus not helical. These regions are thought to be responsible for the immunogenicity associated with most collagen preparations, and this property can, in large part, be mitigated by removal of these regions to produce "atelopeptide" collagen. The removal can be accomplished by digestion with proteolytic enzymes such as trypsin or pepsin. These non-helical atelopeptide regions are however, required to form the cross-links which are responsible for stability of the fibrillar structure in native collagen, since they contain aldehydes capable of cross-linkage; atelopeptide collagen must be cross-linked artificially if it is desired to obtain this characteristic.
Starting from the native material, derived either from bone or from skin, a variety of approaches to the preparation of pure collagenous materials has been disclosed. For example, Battista, U.S. Pat. No. 3,471,598 and 3,632,361 discloses the preparation of a collagen sponge which is a partial salt formed by preparing a dispersion of the collagen salt in an aqueous medium, casting into a mold and freeze drying. This approach is different from that disclosed in U.S. Pat. No. 3,157,524 which describes a collagen reconstituted by reprecipitation of a solubilized tropocollagen (the basic molecular triple helical unit) from a solution. In addition, commercial preparations commonly known as "Collagenfleece" (U.S. Pat. No. 4,066,083) and Avitene provide relatively pure, contiguous collagen preparations which, however, contain atelopeptides and are often immunogenic.
Other preparations of collagen are available commercially. Prominent among these is ZydermŽ collagen implant (ZCI) which is a reconstituted fibrillar suspension of atelopeptide collagen. This preparation is usable in augmenting soft tissue (U.S. Pat. No. 4,424,208) and for cosmetic purposes (when provided as a suspension (U.S. Pat. No. 4,140,537)). The nature of the application to which the collagen preparation is to be put is, of course, instrumental in determining the form of collagen which is most desirable. Certain properties such as, for example, non-immunogenicity are common as desirable to all medical applications. However, other desirable properties vary. For construction of bone replacement material, for example, it would be preferable to have a malleable contiguous mass, whereas for cosmetic "wrinkle-smoothing" applications, an injectable suspension would be preferred. Thus, it is beneficial to provide an arsenal of collagen preparation types whose characteristics offer a spectrum of physical properties.
The present invention adds to the repertoire of available physical properties associated with non-immunogenic collagen preparation.
The present invention provides a malleable, contiguous, elastic form of non-immunogenic collagen which is suitable for a variety of applications. The preparation is characterized on a microscopic scale by interlocking fibrillar ropes having a mean diameter of the order of 170-300 nm, and a microstructure which, within this context, is highly ordered. These physical properties result from a preparation process which employs a secondary nucleation frpm a collagen solution under specified conditions.
Accordingly, in one aspect, the invention concerns a process for preparing a second nucleation form of collagen which process comprises separating a first nucleation product formed by rapid, low temperature mixing of a collagen solution with an insolubilizing buffer, and incubating the remaining collagen in solution to encourage the formation of the desired second nucleation product. The invention, in other aspects, relates to the product of this process, and to collagen preparations having the characteristics associated with it. Included among these characteristics is a microstructure which is predominately formed of interlocking rope-like fibers.
FIG. 1 shows a scanning electron micrograph (reflectance) of the collagen preparation under three different (1000×, 6000×, and 12,000×) magnifications.
FIG. 2 shows a transmission electron micrograph at 30,000× magnification of the collagen preparation of the invention.
"Second nucleation collagen preparation" refers to a collagen precipitated from solution after a first stage precipitation has already taken place. The collagen preparation of the invention is, indeed, formed by a process which involves pre-precipitation of a "first nucleation" preparation followed by treatment of the resulting supernatant to yield the desired product.
A solution "effective in rendering collagen insoluble" refers to a solution which may be added to a solution containing solubilized collagen which will cause the collagen, in principle, to be unstable in solution, and ultimately to precipitate. The precipitation may not be immediate, due to, for example, formation of a supersaturated solution or other metastable condition. In the process of the present invention, the collagen in solution is typically in a solution of approximately pH 2-3 and the protein is soluble indefinitely in the concentrations used at that pH. However, for example, addition of a solution which converts the pH to approximate neutrality will cause the protein eventually to precipitate. However, the precipitation is a relatively slow process, and depends on the conditions of mixing, temperature, and external forces, such as that exerted by centrifugation, in order for the precipitate actually to appear.
The starting material for the preparation of the collagen of the invention is solubilized collagen in a concentration range of 2 mg/ml to 4 mg/ml. A suitable form of this material is an atelopeptide form of bovine skin collagen, which is commercially available from Collagen Corporation, Palo Alto, Calif., ZygenŽ collagen in solution (CIS). This material is a solution containing 3 mg/ml of solubilized collagen at a pH of approximately 2.0. Any solubilized form of collagen can, of course, be used but modifications to the protocols set forth below will undoubtedly be necessary to accomodate to alterations in the starting material. From the standpoint of the physical properties obtained, it may be possible to use collagen which still contains telopeptides; however it is desirable to use an atelopeptide form of solubilized collagen as there would be no particular advantage in using collagen which is known to be immunogenic for medical purposes.
The crux of the process is to form the first nucleation product quickly, under gravitational pressure, and at a temperature gradient in order to provide a supernatant fraction which has the remaining collagen in the correct form for proper formation of the second nucleation batch. To do this, the CIS is rapidly mixed with a solution effective in insolubilizing the collagen--most appropriately a solution which will abruptly raise the pH to approximate neutrality, such as a phosphate buffer of pH above 8. The concentration of the buffer will be compatible with that of the acid components in the CIS so as to result in a final pH of approximately 7 when the appropriate volume is added. It is preferred that the volume ratio of the CIS to that of the added solution be between about 95:5 to 1:1. Each solution is precooled to between 1° C. and 10° C., preferably around 4° C., the two solutions are mixed quickly and the mixture immediately subjected to centrifugation at about 4000×g-16000×g, preferably around 8000×g-13000×g for 1-2 hrs. Thus, during the centrifugation the temperature slowly rises to about room temperature.
As used above, "immediately" refers to a time frame which is in the early lag phase of the fiber formation process. (Collagen fiber formation from solution has been shown to follow a sinusoidal pattern, and it is desired to subject the mixture to the gravitational force before the main thrust of growth phase.) The centrifugation takes place at between about 1° C. to 25° C., preferably around 20° C., and results in a precipitate of between 25% to 60% of the collagen contained in the solution. Optimally, only about 25% of the collagen will precipitate, and the remaining 75% will be available for the second nucleation.
After removal from the centrifuge, the supernatant is gently decanted or otherwise gently removed and incubated at about 15° C.-30° C., preferably around 20° C. from about 4 hrs to about 24 hrs, preferably overnight. During this incubation, the second nucleation preparation forms and is harvested by centrifugation at about 9000 rpm (13,000×g) for about 10 min. Depending on the amount of collagen precipitated during the first nucleation, about 25-60% will be harvested in this second nucleation step. The remaining supernatant will have a concentration of 0.4-0.7 mg/ml, approximately, of collagen, or about 15% of the total.
The desired second nucleation product has a set of physical properties useful in applications where malleable or moldable collagen materials are needed. Specifically, precipitate is characterized by a putty-like texture which is cohesive, and which permits molding with only slight resilience and "memory". There are a number of diagnostic characteristics which indicate the presence of these properties. When examined under a scanning electron microscope as shown in FIG. 1, the molecular structure appears to be composed of intertwining rope-like fibers which have diameters in the range of 170-300 nm. This is especially apparent in FIGS. 1b and 1c which show 6,000 and 12,000 fold magnifications respectively. When subjected to transmission electron microscopy the preparation appears as shown in FIG. 2.
These properties appear to result from the manner of handling the first and second nucleations. In a different, but commercially useful process for preparing ZydermŽ collagen implant (ZCI) dispersions, the same starting material can be used. These dispersions, which are prepared at 35 mg/ml (ZCI-I) and 65 mg/ml (ZCI-II) lack the cohesiveness of the present preparation, and do not show the characteristic rope-like structure. While the chemical conditions of precipitation to form ZCI and the preparation of the invention can be identical, the physical conditions are quite different. The ZCI is precipitated at approximately room temperature, by gradual mixing of the insolubilizing buffer and the fibers are permitted to form without centrifugation. The precipitate harvested from the ZCI precipitation yields approximately 85% of the collagen in the precipitate leaving about 15% in the supernatant, approximately the amount found in the supernatant from the second nucleation product of the invention. Thus, ZCI is a first nucleation product and presumably includes additional collagen which would, in the process of the invention, be left to form the desired product. The precipitate in the ZCI dispersion is harvested, homogenized, and formulated to give the commercially available ZydermŽ collagen implant product. It may also be possible to homogenize or otherwise process and formulate the first nucleation product in the process of the invention; thus providing a convenient utility for a major by-product of the invention.
The following specific preparation procedure illustrates one embodiment of the invention. It is not intended to limit the scope of conditions under which the process can be carried out.
90 ml of ZygenŽ CIS was cooled to 4° C., and quickly mixed in a beaker resting in a 4° C. bath with 10 ml 0.2 M Na2 HPO4 solution which has also been precooled to 4° C. The CIS and phosphate were rapidly thoroughly mixed, and transferred to a centrifuge bottle. The mixture was centrifuged at 10,000×g for 1.5 hrs at 20° C., and the precipitate thus obtained was separated from the supernatant by gentle decantation. The supernatant was then incubated overnight without stirring at 20° C., and the resulting new precipitate harvested by centrifugation at 13,000×g for 10 min. The precipitate was harvested by decanting the supernatant.
The precipitated second nucleation product was then subjected to scanning electron microscopy and transmission electron microscopy, giving the results shown in FIGS. 1 and 2 respectively. It was also tested for melting point and showed a higher melting point than ZCI using differential calorimetry. A dispersion of the resulting collagen was capable, at a concentration of 35 mg/ml to be injected with a number 22 needle.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3131130 *||Jul 31, 1961||Apr 28, 1964||Ethicon Inc||Method of producing soluble collagen|
|US4295894 *||Nov 19, 1979||Oct 20, 1981||Seton Company||Method of preparing soluble collagen fibers|
|US4420339 *||Mar 18, 1982||Dec 13, 1983||Kureha Kagaku Kogyo Kabushiki Kaisha||Collagen fibers for use in medical treatments|
|US4424208 *||Jan 11, 1982||Jan 3, 1984||Collagen Corporation||Collagen implant material and method for augmenting soft tissue|
|US4488911 *||Sep 15, 1983||Dec 18, 1984||Luck Edward E||Non-antigenic collagen and articles of manufacture|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US4655980 *||Mar 13, 1986||Apr 7, 1987||Collagen Corporation||Process of making collagen membranes for medical use|
|US4714758 *||Mar 28, 1986||Dec 22, 1987||Koken Co., Ltd.||Surfactant composed of acylated collagen or acylated gelatine and a production process thereof|
|US4749689 *||Aug 17, 1987||Jun 7, 1988||Koken Co., Ltd.||Hemostatic agent composed of collagen/gelatin and protamine|
|US4776890 *||Apr 3, 1987||Oct 11, 1988||Collagen Corporation||Preparation of collagen hydroxyapatite matrix for bone repair|
|US4840937 *||Sep 16, 1987||Jun 20, 1989||Koken Co., Ltd.||Surfactant composed of acylated collagen or acylated gelatine and a production process thereof|
|US4950483 *||Dec 16, 1988||Aug 21, 1990||Collagen Corporation||Collagen wound healing matrices and process for their production|
|US4969912 *||Feb 18, 1988||Nov 13, 1990||Kelman Charles D||Human collagen processing and autoimplant use|
|US5024841 *||Jun 30, 1988||Jun 18, 1991||Collagen Corporation||Collagen wound healing matrices and process for their production|
|US5110604 *||Dec 19, 1990||May 5, 1992||Collagen Corporation||Processes for producing collagen matrixes and methods of using same|
|US5162430 *||Nov 14, 1989||Nov 10, 1992||Collagen Corporation||Collagen-polymer conjugates|
|US5292802 *||Dec 2, 1992||Mar 8, 1994||Collagen Corporation||Collagen-polymer tubes for use in vascular surgery|
|US5306500 *||Aug 23, 1993||Apr 26, 1994||Collagen Corporation||Method of augmenting tissue with collagen-polymer conjugates|
|US5324775 *||Jul 2, 1992||Jun 28, 1994||Collagen Corporation||Biologically inert, biocompatible-polymer conjugates|
|US5328955 *||Jul 30, 1992||Jul 12, 1994||Collagen Corporation||Collagen-polymer conjugates|
|US5332802 *||Jun 11, 1992||Jul 26, 1994||Autogenesis Technologies, Inc.||Human collagen processing and autoimplant use|
|US5358935 *||Nov 19, 1992||Oct 25, 1994||Robert Allen Smith||Nonantigenic keratinous protein material|
|US5376375 *||Jan 5, 1994||Dec 27, 1994||Collagen Corporation||Method of augmenting tissue using collagen-polymer conjugates|
|US5413791 *||Feb 17, 1994||May 9, 1995||Collagen Corporation||Collagen-polymer conjugates|
|US5446091 *||Jan 5, 1995||Aug 29, 1995||Collagen Corporation||Collagen-polymer conjugates containing an ether linkage|
|US5475052 *||May 2, 1994||Dec 12, 1995||Collagen Corporation||Collagen-synthetic polymer matrices prepared using a multiple step reaction|
|US5510418 *||Nov 3, 1993||Apr 23, 1996||Collagen Corporation||Glycosaminoglycan-synthetic polymer conjugates|
|US5531791 *||Jul 23, 1993||Jul 2, 1996||Bioscience Consultants||Composition for repair of defects in osseous tissues, method of making, and prosthesis|
|US5550188 *||Jun 7, 1995||Aug 27, 1996||Collagen Corporation||Polymer conjugates ophthalmic devices comprising collagen-polymer conjugates|
|US5565519 *||Nov 3, 1993||Oct 15, 1996||Collagen Corporation||Clear, chemically modified collagen-synthetic polymer conjugates for ophthalmic applications|
|US5714582 *||Mar 17, 1995||Feb 3, 1998||Bioscience Consultants||Invertebrate type V telopeptide collagen, methods of making, and use thereof|
|US5800541 *||Jan 8, 1997||Sep 1, 1998||Collagen Corporation||Collagen-synthetic polymer matrices prepared using a multiple step reaction|
|US5807581 *||Sep 29, 1995||Sep 15, 1998||Collagen Corporation||Collagen-based injectable drug delivery system and its use|
|US5814328 *||Jan 13, 1997||Sep 29, 1998||Gunasekaran; Subramanian||Preparation of collagen using papain and a reducing agent|
|US5873906 *||Jul 21, 1997||Feb 23, 1999||Gore Enterprise Holdings, Inc.||Procedures for introducing stents and stent-grafts|
|US5874500 *||Dec 18, 1996||Feb 23, 1999||Cohesion Technologies, Inc.||Crosslinked polymer compositions and methods for their use|
|US5876432 *||Mar 28, 1995||Mar 2, 1999||Gore Enterprise Holdings, Inc.||Self-expandable helical intravascular stent and stent-graft|
|US5919225 *||Jul 14, 1997||Jul 6, 1999||Gore Enterprise Holdings, Inc.||Procedures for introducing stents and stent-grafts|
|US5925061 *||Jan 13, 1997||Jul 20, 1999||Gore Enterprise Holdings, Inc.||Low profile vascular stent|
|US6001123 *||May 28, 1996||Dec 14, 1999||Gore Enterprise Holdings Inc.||Folding self-expandable intravascular stent-graft|
|US6015429 *||Mar 12, 1996||Jan 18, 2000||Gore Enterprise Holdings, Inc.||Procedures for introducing stents and stent-grafts|
|US6017362 *||Jan 22, 1997||Jan 25, 2000||Gore Enterprise Holdings, Inc.||Folding self-expandable intravascular stent|
|US6042605 *||Jul 18, 1997||Mar 28, 2000||Gore Enterprose Holdings, Inc.||Kink resistant stent-graft|
|US6051648 *||Jan 13, 1999||Apr 18, 2000||Cohesion Technologies, Inc.||Crosslinked polymer compositions and methods for their use|
|US6165210 *||Apr 1, 1994||Dec 26, 2000||Gore Enterprise Holdings, Inc.||Self-expandable helical intravascular stent and stent-graft|
|US6166130 *||Apr 30, 1999||Dec 26, 2000||Cohesion Technologies, Inc.||Method of using crosslinked polymer compositions in tissue treatment applications|
|US6323278||Dec 8, 2000||Nov 27, 2001||Cohesion Technologies, Inc.||Method of making crosslinked polymer matrices in tissue treatment applications|
|US6331188||Jun 9, 1997||Dec 18, 2001||Gore Enterprise Holdings, Inc.||Exterior supported self-expanding stent-graft|
|US6337389||Oct 28, 1997||Jan 8, 2002||Bioscience Consultants, L.L.C.||Method and process for the production of collagen preparations from invertebrate marine animals and compositions thereof|
|US6352553||Jul 18, 1997||Mar 5, 2002||Gore Enterprise Holdings, Inc.||Stent-graft deployment apparatus and method|
|US6352561||Dec 23, 1996||Mar 5, 2002||W. L. Gore & Associates||Implant deployment apparatus|
|US6361637||Aug 13, 1999||Mar 26, 2002||Gore Enterprise Holdings, Inc.||Method of making a kink resistant stent-graft|
|US6458889||Jun 15, 2001||Oct 1, 2002||Cohesion Technologies, Inc.||Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use|
|US6517570||Jul 21, 1997||Feb 11, 2003||Gore Enterprise Holdings, Inc.||Exterior supported self-expanding stent-graft|
|US6520986||Jun 26, 2001||Feb 18, 2003||Gore Enterprise Holdings, Inc.||Kink resistant stent-graft|
|US6534591||Aug 17, 2001||Mar 18, 2003||Cohesion Technologies, Inc.||Cross-linked polymer compositions and methods for their use|
|US6548077||Oct 3, 2000||Apr 15, 2003||Subramanian Gunasekaran||Purifying type I collagen using two papain treatments and reducing and delipidation agents|
|US6551350||Dec 23, 1996||Apr 22, 2003||Gore Enterprise Holdings, Inc.||Kink resistant bifurcated prosthesis|
|US6613072||Jul 18, 1997||Sep 2, 2003||Gore Enterprise Holdings, Inc.||Procedures for introducing stents and stent-grafts|
|US6833408||Sep 30, 2002||Dec 21, 2004||Cohesion Technologies, Inc.||Methods for tissue repair using adhesive materials|
|US6911496||Jan 27, 2004||Jun 28, 2005||Cohesion Technologies, Inc.||Composition for administration of a biologically active compound|
|US6916910||Nov 28, 2001||Jul 12, 2005||Bioscience Consultants||Method and process for the production of collagen preparations from invertebrate marine animals and compositions thereof|
|US6969400||Jan 27, 2004||Nov 29, 2005||Cohesion Technologies, Inc.||Synthetic implant with nonimmunogenicity coating|
|US7151135||Mar 10, 2005||Dec 19, 2006||Angiotech Pharmaceuticals (Us), Inc.||Crosslinked polymer compositions|
|US7176256||Jun 21, 2004||Feb 13, 2007||Angiotech Pharmaceuticals (Us), Inc.||Biocompatible crosslinked composition|
|US7682380||Mar 23, 2010||Gore Enterprise Holdings, Inc.||Kink-resistant bifurcated prosthesis|
|US7883693||Jan 31, 2006||Feb 8, 2011||Angiodevice International Gmbh||Compositions and systems for forming crosslinked biomaterials and methods of preparation of use|
|US7883694||Jan 27, 2004||Feb 8, 2011||Angiodevice International Gmbh||Method for preventing the formation of adhesions following surgery or injury|
|US8067031||Apr 28, 2005||Nov 29, 2011||Angiodevice International Gmbh||Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use|
|US8163032||Apr 24, 2012||Kensey Nash Bvf Technology, Llc||Devices and methods for treating defects in the tissue of a living being|
|US8197802||Jun 12, 2012||Angiodevice International Gmbh||Method for treating or inhibiting the formation of adhesions following surgery or injury|
|US8318209||Oct 25, 2005||Nov 27, 2012||Celonova Biosciences Germany Gmbh||Loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same|
|US8323328||Sep 9, 2002||Dec 4, 2012||W. L. Gore & Associates, Inc.||Kink resistant stent-graft|
|US8377466||Feb 19, 2013||Angiotech Pharmaceuticals (Us), Inc.||Adhesive tissue repair patch|
|US8419802||Apr 16, 2013||Kensey Nash Bvf Technology, Llc||Devices and methods for treating defects in the tissue of a living being|
|US8425619||Apr 23, 2013||Kensey Nash Bvf Technology, Llc||Devices and methods for treating defects in the tissue of a living being|
|US8435306||May 7, 2013||Kensey Nash Bvf Technology Llc||Devices and methods for treating defects in the tissue of a living being|
|US8460708||Oct 24, 2011||Jun 11, 2013||Angiodevice International Gmbh||Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use|
|US8481073||Oct 24, 2011||Jul 9, 2013||Angiodevice International Gmbh|
|US8497236 *||Jul 25, 2008||Jul 30, 2013||Zimmer Orthobiologics, Inc.||Implantable putty material|
|US8613938||Nov 15, 2011||Dec 24, 2013||Zimmer Orthobiologics, Inc.||Bone void fillers|
|US8617584||May 25, 2010||Dec 31, 2013||Angiodevice International Gmbh||Adhesive tissue repair patch and collagen sheets|
|US8623065||Oct 7, 2002||Jan 7, 2014||W. L. Gore & Associates, Inc.||Exterior supported self-expanding stent-graft|
|US8623094||Jul 10, 2007||Jan 7, 2014||Kensey Nash Bvf Technology Llc||Devices and methods for treating defects in the tissue of a living being|
|US8690874||Aug 3, 2010||Apr 8, 2014||Zimmer Orthobiologics, Inc.||Composition and process for bone growth and repair|
|US8742072||Mar 29, 2010||Jun 3, 2014||Zimmer Orthobiologics, Inc.||Bone growth particles and osteoinductive composition thereof|
|US9080146||Sep 25, 2008||Jul 14, 2015||Celonova Biosciences, Inc.||Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with a micro-structured surface|
|US9107850||Oct 26, 2007||Aug 18, 2015||Celonova Biosciences, Inc.||Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same|
|US9114162||Oct 24, 2007||Aug 25, 2015||Celonova Biosciences, Inc.||Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same|
|US9248165||Nov 3, 2009||Feb 2, 2016||Hancock-Jaffe Laboratories, Inc.||Composite containing collagen and elastin as a dermal expander and tissue filler|
|US9283074||Apr 4, 2013||Mar 15, 2016||Kensey Nash Bvf Technology, Llc||Devices and methods for treating defects in the tissue of a living being|
|US9326934||May 1, 2012||May 3, 2016||Angiotech International Ag||Drug delivery from rapid gelling polymer composition|
|US20020052572 *||Sep 25, 2001||May 2, 2002||Kenneth Franco||Resorbable anastomosis stents and plugs and their use in patients|
|US20020147154 *||Nov 28, 2001||Oct 10, 2002||Lloyd Wolfinbarger||Method and process for the production of collagen preparations from invertebrate marine animals and compositions thereof|
|US20050004584 *||May 4, 2004||Jan 6, 2005||Cohesion Technologies, Inc.||Resorbable anastomosis stents and plugs and their use in patients|
|US20050165428 *||Feb 25, 2005||Jul 28, 2005||Franco Kenneth L.||Absorable surgical structure|
|US20060088476 *||Oct 25, 2005||Apr 27, 2006||Polyzenix Gmbh||Loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same|
|WO1990005755A1||Nov 21, 1989||May 31, 1990||Collagen Corporation||Collagen-polymer conjugates|
|WO1993016711A1 *||Feb 17, 1993||Sep 2, 1993||Jsf Consultants Ltd.||Use of injectable biomaterials in the treatment of hemorrhoids|
|U.S. Classification||106/160.1, 128/DIG.8, 530/356|
|International Classification||A61L27/24, A61K38/17, C08L89/06, A61F2/00, A61K35/36|
|Cooperative Classification||Y10S128/08, A61L27/24, A61F2310/00365, C08L89/06|
|European Classification||C08L89/06, A61L27/24|
|Sep 5, 1984||AS||Assignment|
Owner name: COLLAGEN CORPORATION 2500 FABER PLACE, PALO ALTO,
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:CHU, GEORGE;REEL/FRAME:004309/0178
Effective date: 19840904
|May 23, 1988||AS||Assignment|
Owner name: COLLAGEN CORPORATION, A CORP. OF DE
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:COLLAGEN CORPORATION, A CA CORP.;REEL/FRAME:004887/0276
Effective date: 19880510
|Mar 20, 1989||FPAY||Fee payment|
Year of fee payment: 4
|May 26, 1993||FPAY||Fee payment|
Year of fee payment: 8
|Jul 15, 1997||REMI||Maintenance fee reminder mailed|
|Dec 7, 1997||LAPS||Lapse for failure to pay maintenance fees|
|Feb 17, 1998||FP||Expired due to failure to pay maintenance fee|
Effective date: 19971210
|Oct 21, 1999||AS||Assignment|
Owner name: ABLECO FINANCE LLC, AS AGENT, NEW YORK
Free format text: SECURITY INTEREST;ASSIGNOR:COLLAGEN AESTHETICS, INC.;REEL/FRAME:010327/0239
Effective date: 19990901